Cyclopentanophenanthrene lactones



United States Patent Ofi 2,705,712 Patented Apr. 5, 1955 ice 2,705,712CYCLOPENTANOPHENANTHRENE LACTONES John A. Ceila, Skokie, Ill., assignorto G. D. Searle & Co., Chicago, 111., a corporation of Illinois NoDrawing. Application September 21, 1953, Serial No. 381,514

5 Claims. (Cl. 260-23957) The present invention relates to 'y-lactonesand alkali metal salts of 3'-[17-(polyhydro-17-hydroxy-15H-cyclopentaEaJphenanthrene)J-acrylic and-propionic acids, and to processes for the preparation of these lactonesand salts from I7-ethynlpolyhydro-17-hydroxy-cyclopenta[a]phenathrenes.More particularly, this invention relates to compounds of the formula s5 7 HO 4 \6 and congeneric 3-0Xo compounds of the formula CH3 IE A ineach of the foregoing formulas being an ethylene (CH vinylene (-CH=CH-)radical. Equivalent to the preceding lactones for the purposes of thisinvention are salts of the corresponding hydroxy acids derived byhydrolytic cleavage of the anhydro ring spinal and various generalanesthetics.

Additionally, the compounds of the delimits the anabolic utility oftestosterone and other naturally-occurring substances known to increasemuscle strength and mass, are uniquely adapted to use in the care ofpremature infants, the management of convalescence from acute illnessand surgical procedures, and for long-term administration to patientswith chronic debilitating disease.

ong the compounds contemplated by the present invention are thoseformulated and named as follows:

(His

3'-[17-(1,2,3,4,7,8,9 10,11,12,13,14,16,17 tetradecahydro-3,17-

dihydroxy 10,1 dimethyl 15H cyclopenta[a]phenanthrene)]-acry1ic acid'y-lactone.

COONa 3'-[17 (1,2,3,4,7,8,9,10,11,] 2,13,14,16,17 tetradecahydro-3,17-dihydroxy 10,13 dimethyl 15H-cyc1openta[a]phenanthrene) J -acrylic acidsodium salt.

CHI

3-[17-(1,2,3,6,7,8,9,10,11,12.13,14,16,17 tetradecahydro-17- hydroxy10,13 dimethy1-3-oxo 15H-cyc1openta [aJphenanthrene)]-acry11c acid-y-lactone.

COOK

3-[17 -(1,2,3,6,7,8,9,1Q,11,12,13,14,16,17 tetradecahydro-17- hydroxy10,13 dlmethyl-3-oxo-15H-cyclopenta[alphenanthrene) ]-acrylic acidpotassium salt.

3'-[17-(1,2,3,4,7,8,9,10,11,12,13,14,16,17 tetradecahydro-3,17-

dihydroxy 10.13 dimethyl 15H-eyclopenta[a]phenanthrene) ]-proplonic acid'y-lactone.

COOK

3'-[17 -(1,2,3,6,7,8,9,10,11,12,13,14,16,17 tetradecahydro-17- hydroxy10,13 dimethyl-3-oxo-15H-cyelopenta[a]phenan threne) ]-propioulc acid'y-laetone.

00 ONa may be converted by the method of Stavely, Journal of theAmerican Chemical Society, 61, 79-80 (1939), using acetylene in thepresence of potassium and tert. amyl alcohol as condensing agents, to a17-ethynyl-1,2,3, 4,7,8,9,10,11,l2,13,14,l6,17 tetradecahydro3,17-dihydroxy 10,13-dimethyl-H-cyclopenta[alphenanthrene, of theformula CH CECE The ethynyl compound, in turn, may be carboxylated afterthe general method of Haynes and Jones, Journal of the Chemical Society,1946, 503-506, whereby the Grignard reagent and carbon dioxide enablethe preparation of a 17-carboxyethynyl-l,2,3,4,7,8,9,l0,l1,12,13,14,16,17 tetradecahydro 3,17 dihydroxy-10,13-dimethyl-15H-cyclopenta[alphenanthrene, the formula of which is CEO-{300E Thelatter compound, upon hydrogenation in the presence of a catalyst suchas palladium on calcium carbonate, or the equivalent, is reduced and, inacid medium, subsequently cyclized to 3-[l7-(1,2,3,4,7,8,9,l0,l1,12,13,14,16,17 tetradecahydro3,17-dihydroxy-10,l3-dimethyl-15H-cyclopentala]phenanthrene)l-acrylicacid 'y-lactone, one of the compounds of this invention. Oppenaueroxidation of this 3-hydroxy lactone, using aluminum isopropoxide,affords another compound of the pres ent invention, namely,3-[l7-(1,2,3,6,7,8,9,l0,11,12,13, 14,16,17 tetradecahydro17-hydroxy-l0,13-dimethyl-3- oxo 15H cyclopenta[a]phenanthrene)l-acrylicacid 7- lactone. Alternatively, the 3-hydroxy lactone above may behydrogenated in the presence of a catalyst such as palladium on carbonpowder to give the 3'-[17-(l,2,3,4,7,8, 9,l0,l1,12,l3,14,16,l7tetradecahydro 3,17-dihydroxy- 10,13 dimethyl15H-cyclopentala]phenanthrene)l-propionic acid -lactone of thisinvention. This lactone may be subjected to Oppenauer oxidation to yieldstill another of the subject compounds, to wit, 3'-[l7-(l,2,3,6,7,8,9,l0,ll,l2,l3,l4,l6,l7 tetradecahydro l7-hydroxy-l0,l3- dimethyl3-oxo-lSH-cyclopentata]phenanthrene)l-propionic acid v-lactone.

The 17 carboxyethynyl 1,2,3,4,7,8,9,10,11,12,13,14, 16.17 tetradecahydro3,17-dihydroxy-l0,l3-dimethyl- 15H-cyclopenta[a]phenanthrene, whichserves as an intermediate for the preparation of compounds of thisinvention, may be converted by Oppenauer oxidation to a 17carboxyethynyl 1,2,3,6,7,8,9,10,l1,12,l3,14,16,l7- tetradecahydro 17hydroxy-lO,l3-dimethyl-3-oxo-15H- cyclopenta[a]phenanthrene, which, likethe claimed com pounds, is a therapeutically valuable material.

The following examples will illustrate in detail certain of theprocesses and products of this invention. However, the invention is notto be construed as limited thereby, either in spirit or in scope, sinceit will be apparent to those skilled in the art of organic synthesisthat many modifications, both of materials and of methods, may bepracticed without departing from the purpose and intent of thisdisclosure. In the examples hereinafter detailed, temperatures are givenin degrees centigrade C.) and relative amounts of materials in parts byweight, except as otherwise noted.

Example I A. 17 carboxyethynvl-I.2,3,4,7,8,9.I0.I1,12,13,14,!6, 17tetradecahydro-3,17-dihydr0xy-I0,13-dimethyl-I5H-cyclonentah]phenanthrene.-The Grignard reagent ofl7-ethynyl-5-androsten-3;8,17,8-diol is prepared by adding a solution of15 parts of the ethynyl compound in approximately 260 parts ofdimethoxyethane to a solution of ethyl magnesium bromide prepared byinteraction of 7.2 parts of magnesium and 33 parts of ethyl bromide, in215 parts of ether. The reactants are maintained at approximately 40 C.until the evolution of ethane gas formed in process effectivelyceases-which is usually after from 2 to 4 hours. Next, the reactionmixture is treated in a bomb at room temperature for 36 hours with 200parts of solid carbon dioxide. Excess carbon dioxide is then vented andthe heterogeneous contents of the bomb thereupon acidified to pH 5. Theresultant three-phase mixture is filtered, and the precipitate thusrecovered is extracted with several 100 cc. portions of hot dioxane. Theinsoluble residue (which is the magnesium bromide salt of the desiredproduct) is then taken up in 50 volumes of an acidified 50-50 mixture ofdioxane and B. 3' [I7 (1,2,3,4,7,8,9,I0,11,12,13,14,16,17 tetradecahydro3,17 dihydr0xy-10,13-dimethyl-15H-cycl0- penta[a]ph.enanthrene)J-acrylic acid 'y-l act0ne.-A solut e reaction mixturethereupon filtered to remove catasuflicient 1% aqueous The solid productthus obtained is filtered off and then crystallized from 20-30 volumesof 80% aqueous methyl alcohol. The purified material,3'-[l7-(1,2,3,4,7,8,9,10,11,12,13, 14,16,17tetradecahydro-3,17-dihydroxy-10,13-dimethyl-15HFcyclopenta[a]phenanthrene)J-acrylic acid 'y-lactone, shows M. P.197.520l C., hid-[ 2 (in chloroform).

Example 2 3'-[17-(1,2,3,6,7,8,9,10,11,12,13,14,16,1 7tetradecahydro-I7-hydr0xy 10,13 dimethyl 3 0x0 15H cyclopenta a]phenanthrene) -acrylic acid 'y-laclone.The 3-hydroxy lactone of thepreceding Example 13 may be converted to the corresponding 3-oxocompound by Oppenauer oxidation according to the following procedure: 4parts of the starting B-hydroxy lactone is dissolved in a mixture of 220parts of dry toluene and 24 parts of cyclohexanone. This solution isrefluxed for 1 hour with approximately one-third its volume of aluminumisopropoxide in dry toluene. drolyzed by addition of a saturated aqueoussolution of Rochelle salts, then steam distilled to remove solvent. Thedistalland is extracted with chloroform to remove the oil precipitatedtherein, and the chloroform extract is then dried and finally evaporatedto dryness. The residue is purified by chromatographic adsorption onsilica gel, using benzene and ethyl acetate as developing solvents. Thematerial chrystallization from a 50-50 mixture of ethyl acetate andcyclohexane. The 3'-[l7-(1,2,3,6,7,8,9,10,l1,12,13,14,16,17-tetradecahydro-17-hydroxy 10,13 dimethyl-3-oxo-ISH-cycIopenta[a]phenanthrene) ]-acrylic acid -lactone prepared inthis manner shows M. P. 1535-1545 C., [a] +203.5 (in chloroform).

Example 3 3-[17-(I,2,3,4,7,8,9,10,I1,I2,I3,14,16,17tetradecahydr0-3,17-dihydr0xy-]0,13-dimethyl H cyclopenta [a]phenanthreneH-propionic acid 'y-lactone.-A solution of 1 part of the3-hydroxy lactone of Example 1B in 50 volumes of alcohol is hydrogenatedat atmospheric pressure and room temperature in the parts of methylethyl ketone yields the desired 3-[l7-l,2,3,4,7,8,9,10,l1,l2,13,l4,16,17 tetradecohydro-3,17-dihydroxy-10,l3-dimethyl 15H cyclopenta[a]phenanthrene) ]-propionic acid-y-lactone as a pure product. The material shows M. P. I87189 C.

minutes with aluminum isopropoxide in is refluxed for 20 20% drytoluene. A saturated aqueous solution of Rochelle the reaction product,wheresteam distilled to remove solvent. e oily product precipitated inthe distilland is exsired3-[17-(1,2,3,6,7,8,9,10,1l,l2,13,14,16,17-tetradecahydro-17-hydroxy-l0,13-dimethyl-3-oxo-15H- cyclopenta [a]phenanthrene)J-propionic acid 'y-lactone, which iscrystallized from a mixture consisting of 2 parts of ethyl acetate and 3parts of petroleum ether. The product shows M. P. 148-149 C.

I claim:

1. A compound selected from the group consisting of compounds of theformula A in each of the foregoing formulas being selected from thegroup consisting of ethylene and vinylenc radicals.

2. 3'- [17- (1,2,3,4,7,8,9,l0,11,12,13,14,16,17tetradecahydro-3,17-dihydroxy 10,13dimethyl-ISH-cyclopenta[a]phenanthrene)J-acrylic acid 'y-lactone, havingthe formula CH: O

3. 3' [17(l,2,3,6,7,8,9,l0,l1,12,13,14,16,17-tetradecahydro-l7-hydroxy-l0,13-dimethyl -3- oxo-lSH-cyclopentaialphenanthrene)J-acrylic acid'y-lactone, having the formula mm) CH3 0 4. 3' [17(1,2,3,4,7,8,9,10,11,12,13,14,16,17-tetradecahydro 3,17 hydroxy 10,13dimethyl-lSH-cyclo- 8 pcnt a[a]phenanthrcnc)l-propionic acid 'y-lactone,havpentakilphenanthrene)J-propionic acid 'y-lactonc, having the fprmulamg the formula OH: CH,

CH: 0 CH: O

no 0: 5. 3' [17 (1,2,3,6,7,8,9,10,11,12,13,14,16,17-tetIa- 15decahydro-17-hydroxy-10,13-dimethy1-3-oxo-1SH cyclo- N0 referencescited.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFORMULA